The neurodegenerative disorders characterized by protein aggregation include nine untreatable diseases caused by CAG/glutamine tract expansions. One of these polyglutamine (polyQ) diseases, spinobulbar muscular atrophy (SBMA), is a degenerative disorder of lower motor neurons caused by a mutation in the androgen receptor (AR) gene. The mutant protein undergoes hormone-dependent nuclear translocation, unfolding and oligomerization, steps that are critical to toxicity and to the development of progressive proximal limb and bulbar muscle weakness in men. Although the disease causing mutation was identified about two decades ago, mechanisms that are central to the pathogenesis of SBMA remain poorly understood and available therapies are largely supportive. Recent studies demonstrate that post-translational modifications of the AR triggered by ligand influence toxicity. Our laboratory has shown that conjugation of the polyQ AR by SUMO (small ubiquitin-like modifier) impairs ligand-dependent oligomerization of the mutant protein. However, the extent to which this modification alters the disease phenotype in vivo is currently unknown. The objective of this application is to determine the extent to which SUMOylation of the polyQ AR affects SBMA pathogenesis. Our central hypothesis is that SUMOylation of the polyQ AR diminishes neuromuscular toxicity in SBMA. This hypothesis springs from our own preliminary data demonstrating that SUMOylation decreases the levels of soluble AR oligomers and aggregates in cellular models of SBMA. Here we will use gene targeting to generate knock-in mice expressing a SUMO resistant polyQ AR to determine the extent to which this pathway affects disease pathogenesis. The rationale of the proposed work is that defining the role of the SUMOylation pathway in disease will yield insights into pathogenic mechanisms and accelerate the discovery of targets for disease- modifying therapies. Genetic and biochemical approaches will be combined with characterization of mouse behavioral and neuropathological changes to establish the effects of polyQ AR SUMOylation in a knock-in mouse model of SBMA. These studies are expected to have a significant positive impact by defining the role of SUMOylation in SBMA and thereby identifying potential therapeutic targets. As several neurodegenerative disease-causing proteins are targeted by SUMO, we anticipate that our findings will also serve as a paradigm for understanding the effects of SUMOylation on the phenotype of these related disorders.